Chemoreceptive and mechanoreceptive mechanisms in the duodenum play an important role in the regulation of gastric motility. Following ingestion of a meal as chyme enters the duodenum, stimulation by osmolarity and mechanical distension may activate vagal affrent fibers in the mucosa resulting in gastric relaxation and inhibition of gastric motility. Abnormalities in this neural pathway may be a cause of functional dyspepsia. Currently little is known about the neural circuits responsible for these vago-vagal reflexes. Based on our preliminary studies, we hypothesize that hyperosmolar chyme and mechanical distension stimulate the release of serotonin (5-HT) from intestinal EC cells which act as a sensor for luminal stimuli. 5-HT in turn activates vagal afferent fibers releasing substance P or CGRP which then stimulates interneurons in the nucleus tractus solitarius (NTS). Two groups of NTSA neurons interacting with the dorsal vagal motor nucleus (DMNV) will be stimulated: (i) activation of GABAergic neurons will inhibit DMNV cholinergic neurons which synapse with intragastric cholinergic neurons and (ii) stimulation of glutaminergic neurons will activate those DMNV neurons which synapse with intragastric nitric oxide neurons. In this manner the vagal afferents may concurrently excite and inhibit vagal efferent transmission producing dysfacilitation of cholinergic and activation of NANC input to the stomach to optimize gastric relaxation. To test this hypothesis, we will examine the neural pathways utilized by duodenal distension and stimulation by hyperosmolar solutions to mediate gastric relaxation. The role of 5-HT in the mediation of activation of vagal sensory fibers by these duodenal stimuli will be investigated. We will characterize the chemical codings by intracellular recording and labeling techniques. In vitro electrophysiological analysis of the NTS and DMNV synaptic relationship will be performed using medullary slices. The possibility of glutamate and GABA as excitatory and inhibitory neurotransmitters to turn on and off populations of neurons in the DMNV during activation by serotonin or duodenal stimulation will be assessed. These studies will provide a detailed characterization of the neural components of the vago-vagal circuit activated by duodenal distension and hyperosmolar solution to mediate gastric relaxation. This information may help to elucidate the pathophysiology of functional dyspepsia and lead to the development of novel therapies.